Obesity is a state having excessive body weight (especially, white adipose tissues), and in general, classified by Body Mass Index (BMI)≧25 kg/m2 and further classified by a body fat percentage of 25% or more for adult males and 30% or more for adult females. In these days of the dietary habit loaded with high-fat foods and the lack of exercise, the percentage of people classified into obese tends to increase. The results of National Nutrition Survey by the Ministry of Health, Labour and Welfare in 2000 indicate that males classified into the obese have definitely increased in comparison with that in the last decade and two decades, and around 30% of the males from 40 to 69 years old are classified into the obese. Further, in females, around 30% of the females from 60 to 69 years old are also classified into the obese.
Currently, health disorder (capable of being) associated with obesity other than the obesity itself is clinically a large issue, and forms a medical reason for the prevention or treatment of obesity. The Japan Society for the Study of Obesity defines adiposis as “a pathological condition complicating health disorder that is caused by or associated with obesity, or medically requiring weight reduction when the complication is clinically predicted” and advocates to treat it as a disease. In “health disorder” herein described, in addition to type 2 diabetes mellitus and impaired glucose tolerance, hypertension, hyperlipemia, hyperuricemia, fatty liver, cardiovascular/cerebrovascular disease, sleep apnea syndrome, orthopedic disease such as osteoarthritis and the like, menstrual disorder and others are included (Yuji Matsuzawa, Nippon-Rinsho, Nippon Rinsho Co., Ltd., “Obesity” extra No. 6, Vol. 61, p5-8, Jul. 28, 2003). In addition, it is reported that as a disease caused by obesity, malignant tumors are mentioned, and obesity is a risk factor for the onset of especially breast cancer, uterus cancer, colon cancer, kidney cancer, esophagus cancer, pancreas cancer, hepatic cancer and gallbladder cancer (Yuji Matsuzawa, Nippon-Rinsho, Nippon Rinsho Co., Ltd., “Obesity” extra No. 6, Vol. 61, p5-8, Jul. 28, 2003; Abu-Abid et al., Journal of medicine (MSA), Vol. 33, No. 1-4, p73-86, Jan. 1, 2002; Nair et al., Hepatology (MSA), Vol. 36, No. 1, p150-155, Jul. 1, 2002). Further, in recent years, a combined risk syndrome that is referred to as a metabolic syndrome and increases the risk of an arteriosclerotic disease (myocardial infarction, cerebral infarction and the like) has been proposed and has drawn the attention for the fact that 30% in total mortality is caused by cerebral vascular disorder and vascular disorder in Japan. Therefore, the diagnostic criteria were established jointly by the Japan Society for the Study of Obesity, the Japan Atherosclerosis Society, the Japan Diabetes Society, the Japanese Society of Hypertension, the Japanese Circulation Society, the Japanese Society of Nephrology, the Japanese Society on Thrombosis and Hemostasis, and the Japanese Society of Internal Medicine and published at the press conference in the Japanese Society of Internal Medicine on 8 Apr. 2005. According to the diagnostic criteria, a metabolic syndrome is diagnosed in the case of having two or more risks among the risks of impaired serum lipid (having either or both a triglyceride level of 150 mg/dL or more and/or an HDL cholesterol level of less than 40 mg/dL), high blood pressure (having either or both a systolic blood pressure of 130 mmHg or more and/or a diastolic blood pressure of 85 mmHg) and high blood sugar (a fasting blood sugar level of 110 mg/dL or more), in addition to having a waist circumference of 85 cm or more for males and 90 cm or more for females, while setting the visceral obesity (visceral fat accumulation) in the center of the risks (Journal of Japanese Society of Internal Medicine, Exploratory Committee for Diagnostic Criteria of Metabolic Syndrome, Vol. 94, April issue in 2005, p794-809). There is also a report that, when the diagnostic criteria are applied, among the adult males who had a complete medical checkup, while 61 males (21%) were diagnosed with adipositas, 27 males (9%) were diagnosed with metabolic syndrome and even 9 males (3%) were diagnosed with metabolic syndrome without being included in adiposis (Kazuo Takahashi, Yasushi Saito, Igaku no Ayumi, Vol. 213, No. 6, p549-554, 2005).
As opposed to the obesity, excessive weight loss (what is called “skinny”) and decreased food intake (what is called “decreased appetite”) become a problem as a factor of easy infection caused by reduced-biological defense (immune) response, hematopoietic disorder, amenorrhea or irregular menstruation, infertility, psychical disorder, peripheral nerve paralysis, hypotension, osteoporosis and the like. In general, when the BMI is <18.5 kg/m2, or the body fat percentage is 10% or less for males and 15% or less for females, the males/females are classified into “skinny”. In the National Nutrition Survey by the Ministry of Health, Labour and Welfare in 2000, the ratio of the females having BMI <18.5 kg/m2 has steadily increased between 20 and 39 years old during the last decade and two decades, and around 24% of the females between 20 and 29 years old are classified into “skinny”. This may be caused in young females by intentionally regulating the amount of food intake with a concern for their body shapes. However, in the case of anorexia nervosa (anorexia) and the like among the food intake abnormalities of central origin that occur frequently in this age group, the appetite itself is significantly decreased, and the nutritional status is compromised, as a result, the general debility may cause death. Further, as a disease causing a decrease of appetite and including the concept that is conventionally referred to as descensus ventriculi, gastric atony and neurotic gastritis, there is a disease referred to as “Functional dyspepsia”, and the disease is said to exhibit a symptom such as an early satiety sensation after eating, a loss of appetite and the like (Talley et al., Gut (England), Vol. 45, Suppl. 2, p1137-1142, 1999). Furthermore, a factor causing a decreased appetite is exemplified by a cancer, an inflammatory disease, a decline in the function of pituitary gland, thyroid gland, adrenal gland and the like, after surgery, an extreme stress, and others. Under such conditions, by a decreased appetite persisting for a long time, wasting of the body is brought about.
In these circumstances, biological factors regulating food intake are recently actively studied and the relation between a factor such as leptin, adiponectin, ghrelin and the like and the food intake regulation is also studied. In recent years, as a substance associated with food intake and obesity, Nesfatin-1 is reported (Oh-I S. et al., Nature, 443(7112):709-12, 2006), and which is expected as a novel factor involved in the food intake regulation and/or body weight regulation.
A receptor of a certain factor is useful in search for a substance having action similar to such factor or a substance regulating the action of such factor, and is frequently tried to be isolated. However, isolation of the receptor is usually difficult, since the interaction between factor and receptor differs depending on the type of the cells on which such factor acts and the environment in the tissue where the cells are placed. Further, even when the factor has similar action, the factor does not always have a similar receptor structure, and therefore the receptor structure is extremely difficult to be predicted from the factor action.
For example, for leptin that is a biological factor regulating food take, the presence of its receptor is known, but the receptor is a single-transmembrane receptor and known to have a similar structure to that of gp130 that is a signal transduction molecule common to a cytokine receptor such as IL-6, G-CSF, LIF and the like. On the other hand, a receptor of Nesfatin-1 had not been reported yet, and the elucidation has been expected.
A G-protein-coupled receptor (hereinafter, abbreviated as “GPCR”) refers to as a receptor group that couples to G proteins to conduct signal transduction, and has a characteristic common structure in which such receptor passes through cell membrane 7 times. In such GPCR, various responses such as hormone, neurotransmitter substances, sensory stimuli and the like are known over the wide range. Among them, in several GPCRs, the relationship with obesity has been reported (Xu et al., European Journal of Pharmacology 500: 243-253, 2004).
In Bjursell M et al., Biochemical and Biophysical Research Communication, 348(2): 359-366, 2006, it is reported that in a GPCR12 (hereinafter, also referred to as GPR12)-KO mouse, the weight gain, the white adipose increase and the like were exhibited, but the food intake was not affected at all, and it is suggested that GPR12 may be involved in a low-energy consumption. Further, this GPR12 is known to form a family with GPR3 and GPR6. In Non-Patent Uhlenbrock K et al., Cellular Signaling, 14(11): 941-953, 2002, it is reported that sphingosine 1-phosphate (hereinafter, abbreviated as “S1P”) is an endogenous ligand of GPR12. In Ignatov A et al., The Journal of Neuroscience, 23(3): 907-914, 2003, it is reported that sphingosylphosphorylcholine (hereinafter, abbreviated as “SPC”) is an endogenous ligand of GPR12.